The present invention relates to compounds that bind to and affect PPAR gamma. In another aspect, the present invention relates to methods for prevention or treatment of PPARgamma mediated diseases and conditions and to a method for prevention or treatment of osteoporosis.
Peroxisome Proliferator Activated Receptors (PPARs) are orphan receptors belonging to the steroid/retinoid receptor superfamily of ligand-activated transcription factors. See, for example, Willson, T. M. and Wahli, W., Curr. Opin. Chem. Biol., (1997), Vol. 1, pp 235-241.
Three mammalian PPARs have been identified which are termed PPAR-alpha, PPAR-gamma, and PPAR-delta. PPARs regulate expression of target genes by binding to DNA response elements as heterodimers with the retinoid X receptor. These DNA response elements (PPRE) have been identified in the regulatory regions of a number of genes encoding proteins involved in lipid metabolism and energy balance. The biological role of the PPARs in the regulation of lipid metabolism and storage has been recently reviewed. See, for example, Spiegelman, B. M., Diabetes, (1998), Vol. 47, pp 507-514, Schoonjans, K., Martin, G., Staels, B., and Auwerx, J., Curr. Opin. Lipidol., (1997), Vol. 8, pp 159-166, and Brun, R. P., Kim, J. B., Hu, E., and Spiegelman, B. M., Curr. Opin. Lipidol., (1997), Vol. 8, pp 212-218.
PPAR-gamma ligands of the thiazolidinedione class (TZD) enhance the actions of insulin in man and reduce circulating glucose levels in rodent models of diabetes. The PPAR-gamma receptor is expressed in adipose tissue and plays a pivotal role the regulation of adipocyte differentiation in vitro. TZD such as rosiglitazone induce adipocyte differentiation in vitro through activation of the PPAR-gamma receptor. Thus, although there are clearly therapeutic uses for PPAR-gamma ligands in the treatment of diseases of lipid metabolism and energy balance, it is possible that there will be side effects of these drugs. For example, PPAR-gamma ligands that promote adipocyte differentiation in vivo could lead to increased fat accumulation and weight gain. This side effect might offset the beneficial effects of a PPAR-gamma ligand in the treatment of diabetes or other diseases where obesity is a risk factor. See, for example, the Spiegelman and Brun articles cited above.
Essential dietary fatty acids and certain of their eicosanoid metabolites are naturally occurring hormones for the PPAR-gamma receptor. These hormones can promote adipogenesis through activation of the PPAR-gamma receptor. See, for example, Kliewer, S. A., et al., Proc. Natl. Acad. Sci. USA, (1997), Vol. 94, pp 4318-4323, and Kliewer, S. A., et al., Cell, (1995), Vol. 83, pp 813-819. Molecules that inhibit the adipogenic effects of endogenous PPAR-gamma hormones may be useful in the treatment of diseases caused by increased fat accumulation or lipid storage. See, for example, Tontonoz, P., Hu, E., and Spiegelman, B. M., Curr. Opin. Genet. Dev., (1995), Vol. 5, pp 571-576. Examples of these diseases are obesity, osteoporosis, and acne. For example, it has also been noted that TZD promote adipogenesis in bone marrow and inhibit expression of markers of the osteoblast phenotype such as alkaline phosphatase. See, for example, Paulik, M. A. and Lenhard, J. M., Cell Tissue Res., (1997), Vol. 290, pp 79-87. These effects may lead to low bone mineral density and osteoporosis. Compounds that promote osteogenesis activity may be useful in the treatment of osteoporosis. Similarly, it is known that the TZDs can promote lipid accumulation in sebocytes. See, for example, Rosenfield, R. L., Deplewski, D., Kentsis, A., and Ciletti, N. Dermatology, (1998), Vol. 196, pp 43-46. These effects may lead to sebocyte differentiation and acne formation. Thus, molecules that block adipogenesis in adipocytes, pre-adipocytes, bone marrow, or sebocytes may have beneficial effects in the treatment of obesity, osteoporosis, or acne.
The PPAR-gamma receptor has been found in tissues other than adipose, and it is believed that synthetic PPAR-gamma ligands and natural PPAR-gamma hormones (natural ligands) may have beneficial effects in many other diseases including cardiovascular disease, inflammation, and cancer. See, for example, the Schoonjans article cited above, Ricote, M. et al., Nature, (1998), Vol. 391, pp 79-82, and Mueller, E. et al., Mol. Cell, (1998), Vol. 1, pp 465-470.
There is precedent among other member of the steroid/retinoid receptor superfamily that synthetic ligands can be identified which mimic many of the beneficial effects but inhibit some of the detrimental side effects of the natural hormones. See, for example, McDonnell, D. P., Biochem. Soc. Trans., (1998), Vol. 26, pp 54-60. These synthetic ligands have been given various labels, including antagonists, anti-hormones, partial agonists, selective receptor modulators, tissue selective ligands, and others. See, for example, Katzenellenbogen, J. A., O""Malley, B. W., and Katzenellenbogen, B. S., Mol. Endocinol., (1996), Vol. 10, pp 119-131.
As used herein, a xe2x80x9cPPARgamma ligandxe2x80x9d is a compound that binds to human PPARgamma with a pKi of greater than 5 when tested in the binding assay described below. As used herein a xe2x80x9cPPARgamma antagonistxe2x80x9d is a PPARgamma ligand that gives greater than 50% inhibition of lipogenesis when tested in the adipocyte differentiation assay described below and greater than 50% inhibition of transactivation by rosiglitazone when tested in the cell-based reporter assay described below.
Briefly, in one aspect, the present invention discloses compounds of Formula (I) and pharmaceutically acceptable salts and solvates thereof, 
where n is 2, 3, or 4,
R1 is hexyl, heptyl, or C4-6alkyl-phenyl,
R2 is butyl or benzyl optionally substituted with 1 or 2 halogen,
R3 is butyl, benzyl optionally substituted with a trifluoromethyl group or with 1 to 3 halogen, xe2x80x94C4H8OH, p-pyridyl, o-pyridyl, ethylpropionate, propyl, ethyl acetate,
o-thiophenmethyl, 2,3-methylenedioxobenzyl, 2-thiazolemethyl, 2-furfuryl,
R4 is xe2x80x94COOH, xe2x80x94NHC(O)NH2, xe2x80x94NHS(CH3)O2, xe2x80x94S(NH2)O2), hydantoin, xe2x80x94OH, xe2x80x94OCH2CO2H, xe2x80x94OCH2CONH2, xe2x80x94OCH3,
R5 is hydrogen or R5 and R4 are bonded together to form a methylenedioxo ring.
In another aspect, the present invention discloses a method for prevention or treatment of a PPARgamma mediated disease or condition comprising administration of a therapeutically effective amount of a compound of this invention. As used herein, xe2x80x9ca compound of the inventionxe2x80x9d means a compound of formula (I) or a pharmaceutically acceptable salt, or solvates thereof. Particular diseases or conditions are diabetes, obesity, dyslipidemia, metabolic syndrome, osteoporosis, acne, cardiovascular disease, inflammation or cancer.
In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention, preferably in association with a pharmaceutically acceptable diluent or carrier.
In another aspect, the present invention discloses a method for prevention or treatment of osteoporosis comprising administration of a therapeutically effective amount of a PPARgamma antagonist.
In another aspect, the present invention provides a compound of the invention for use in therapy, and in particular, in human medicine.
In another aspect, the present invention provides the use of a compound of the invention for the manufacture of a medicament for the treatment of a PPARgamma mediated disease or condition. Particular diseases or conditions are diabetes, obesity, dyslipidemia, metabolic syndrome, osteoporosis, acne, cardiovascular disease, inflammation or cancer.
In another aspect, the present invention provides the use of a PPARgamma antagonist for the manufacture of a medicament for the treatment of osteoporosis.
In another aspect, the present invention provides a method for identifying compounds that will be useful for the treatment of a PPAR gamma mediated disease or condition, comprising the step of binding a compound of this invention to PPAR gamma.
In another aspect, the present invention provides a method for treating a PPAR gamma mediated disease or condition comprising administration of a therapeutically effective amount of a compound that was identified as useful for such treatment by the above method (in other words, by a method comprising the step of binding a compound of this invention to PPAR gamma).
In another aspect, the present invention provides the use of a compound that was identified as useful for treating a PPAR gamma mediated disease or condition by the above method (in other words, by a method comprising the step of binding a compound of this invention to PPAR gamma), for the manufacture of a medicament for the treatment of a PPAR gamma mediated disease or condition.
In another aspect, the invention provides a method for identifying compounds which will be useful in treatment of osteoporosis comprising the step of determining whether a compound antagonises PPAR gamma.
Preferably, when any of the R groups in Formula (I) are alkyl, they are straight chain alkyl.
Preferably, R3 is butyl, benzyl optionally substituted with 1 or 2 halogen, or p-pyridyl.
Suitable compounds of the present invention include:
4-(4-(4-carboxyphenyl)butyl)-2-heptyl4-oxo-5-thiazolidine N,N-dibenzylacetamide,
(2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,
(2S,5S)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,
(2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-hexyl-4oxo-5-thiazolidine N,N-dibutylacetamide,
(2S*,5S*)-4-(2-(4-carboxyphenyl)ethyl)-2-octyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,
(2R*,5S*)-4-(2-(4-carboxyphenyl)ethyl)-2-octyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,
(2S*,5S*)-4-(2-(4-carboxyphenyl)ethyl)-2-octyl-4-oxo-5-thiazolidine N,N-di-(3-iodo)benzylacetamide,
(2S*,5S*)-4-(3-(4-carboxyphenyl)propyl)-2-heptyl-4-oxo-5-thiazolidine N,N-benzylacetamide,
(2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N,N-di-(3-benzylacetamide,
(2S*,5S*)-4-(2-(4-carboxyphenyl)ethyl)-2-(6-phenylhexyl)-4-oxo-5-thiazolidine N,N-dibenzylacetamide,
(2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-(6-phenylhexyl)-4-oxo-5-thiazolidine N,N-dibenzylacetamide,
4-(4-(4-carboxyphenyl)butyl)-2-(4-phenylbutyl)-4-oxo-5-thiazolidine N,N-dibenzylacetamide,
(2S*,5S*)-4-(2-(4-ureidophenyl)ethyl)-2-octyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,
(2S,5S*)-4-(2-(4-methylsufonamidophenyl)ethyl)-2-octyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,
(2S*,5S*)-4-(2-(4-aminosulfonylphenyl)ethyl)-2-octyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,
(2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N-benzyl-N-(4-trifluorobenzyl)acetamide,
(2R*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N-benzyl-N-4-trifluorobenzyl)acetamide,
(2S*,5S*)-4-(2-(4-(3-hydantoino)phenyl)ethyl)-2-octyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,
(2S*,5S*)-4-(2-(3,4-dioxomethylenephenyl)ethyl)-2-heptyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,
(2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-octyl-4-oxo-5-thiazolidine N-benzyl-N-(4-hydroxybutyl)acetamide,
(2S*,5S*)-4-(2-(3,4-dioxomethylenephenyl)ethyl)-2-octyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,
(2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N-benzyl-N-(4-pyridyl)acetamide,
(2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N-benzyl-N-(2-pyridyl)acetamide,
(2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N-benzyl-N-(2-ethoxycarboxyethyl)acetamide,
(2S*,5S*)-4-(4-(4-(carboxyphenyl)butyl)-2-heptyl-4-oxo-5 -thiazolidine N-benzyl-N-butylacetamide,
(2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N-benzyl-N-isopropylacetamide,
(2S*,5S*)-4-(2-(4-hydroxyphenyl)ethyl)-2-heptyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,
(2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N-benzyl-N-ethoxycarboxymethylacetamide,
(2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N,N-di-(4-fluorobenzyl)acetamide,
(2S*,5S*)-4-(2-(4-carboxymethoxyphenyl)ethyl)-2-heptyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,
(2S*,5S*)-4-(2-(4-carboxyamidomethoxyphenyl)ethyl)-2-heptyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,
(2S*,5S*)-4-(2-(4-methoxyphenyl)ethyl)-2-heptyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,
(2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N-benzyl-N-(2-thienylmethyl)acetamide,
(2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N-benzyl-N-(2,3-dioxomethylenebenzyl)acetamide,
(2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N-benzyl-N-(2-thiazolemethyl)acetamide,
(2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N-benzyl-N-(2-furfuryl)acetamide, and pharmaceutically acceptable salts and solvates thereof.
Particularly preferred compounds of the present invention include:
(2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,
(2S,5S)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,
(2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-hexyl-4-oxo-5-thiazolidine N,N-dibutylacetamide,
(2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-octyl-4-oxo-5-thiazolidine N-benzyl-N-(4-hydroxybutyl)acetamide,
(2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N-benzyl-N-(4-pyridyl)acetamide,
(2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N-benzyl-N-(2-thiazolemethyl)acetamide, and pharmaceutically acceptable salts and solvates thereof.
Those skilled in the art will recognise that stereocenters exist in compounds of Formula (I). Accordingly, the present invention includes all possible stereoisomers and geometric isomers of formula (I) and includes not only racemic compounds but also the optically active isomers as well. When a compound of formula (I) is desired as a single enantiomer, it may be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or any convenient intermediate. Resolution of the final product, an intermediate or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Carbon Compounds by E. L. Eliel (Mcgraw Hill, 1962) and Tables of Resolving Agents by S. H. Wilen. Additionally, in situations where tautomers of the compounds of formula (I) are possible, the present invention is intended to include all tautomeric forms of the compounds.
While the compounds of this invention include all enantiomers and diastereomers, the trans pair of diastereomers is preferred. This pair consists of the (2S, 5S) enantiomer and the (2R, 5R) enantiomer. This diastereomer pair will be abbreviated as (2S*,5S*). Most preferred are the (2S,5S) enantiomers.
It will also be appreciated by those skilled in the art that the compounds of the present invention may also be utilised in the form of a pharmaceutically acceptable salt or solvate thereof. The physiologically acceptable salts of the compounds of formula (I) include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or bases as well as quaternary ammonium acid addition salts. More specific examples of suitable acid salts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, pamoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic, naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts. More specific examples of suitable basic salts include sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine salts. References hereinafter to a compound according to the invention include both compounds of Formula (I) and their pharmaceutically acceptable salts and solvates.
It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established diseases or symptoms. Moreover, it will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general, however, doses employed for adult human treatment will typically be in the range of 0.02-5000 mg per day, preferably 1-1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
While it is possible that compounds of the present invention may be therapeutically administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation. Accordingly, the present invention further provides for a pharmaceutical formulation comprising a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, preferably together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredients.
Formulations of the present invention include those especially formulated for oral, buccal, parenteral, transdermal, inhalation, intranasal, transmucosal, implant, or rectal administration, however, oral administration is preferred. For buccal administration, the formulation may take the form of tablets or lozenges formulated in conventional manner. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, (for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol), lubricants (for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (for example, potato starch or sodium starch glycollate) or wetting agents, such as sodium lauryl sulfate. The tablets may be coated according to methods well known in the art.
Alternatively, the compounds of the present invention may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, for example. Moreover, formulations containing these compounds may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents such as lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives such as methyl or propyl p-hydroxybenzoates or sorbic acid. Such preparations may also be formulated as suppositories, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. Additionally, formulations of the present invention may be formulated for parenteral administration by injection or continuous infusion. Formulations for injection may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle (e.g., sterile, pyrogen-free water) before use.
The formulations according to the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Accordingly, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (as an emulsion in an acceptable oil, for example), ion exchange resins or as sparingly soluble derivatives as a sparingly soluble salt, for example.
The formulations according to the invention may contain between 0.1-99% of the active ingredient, conveniently from 30-95% for tablets and capsules and 3-50% for liquid preparations.
The novel thiazolidine acetamides of this invention can be used to inhibit adipogenesis. Surprisingly, it has been found that PPARgamma ligands that inhibit adipogenesis also stimulate alkaline phosphatase activity, which is a surrogate marker for stimulation of osteogenesis. In addition to this activity, these novel PPAR-gamma ligands maintain many of the beneficial effects of known PPAR-gamma ligands, such as antidiabetic activity.
Thus, synthetic PPAR-gamma ligands that block adipogenesis while mimicking the beneficial effects of natural PPAR-gamma hormones will be useful for the treatment of human disease, including diabetes, obesity, dyslipidemia, metabolic syndrome, osteoporosis, acne, cardiovascular disease, inflammation, or cancer.
The compounds of this invention can be prepared by standard organic chemistry as illustrated by the accompanying working examples. The following examples are set forth to illustrate the synthesis of some particular compounds of the present invention and to exemplify general processes. Accordingly, the following Examples section is in no way intended to limit the scope of the invention contemplated herein.